The proposed Program Project is designed to determine the molecular basis of HIV-1 associated encephalopathy. The Program utilizes several novel experimental models and techniques to elucidate the interaction of HIV-1 with human neural tissue. These include new systems to study highly permissive and non-permissive HIV-1 replication in neural cells in vitro, a model for neuronotoxin induction involving HIV-1 infected macrophages, an explant model of developing human brain, and two polymerase chain reaction-based systems for testing HIV-1 involvement directly (ex vivo) in brain section of HIV-1 infected children. Throughout this Program, we intend to test two distinct, but complementary routes to HIV-1 associated neuropathogenesis: through direct effects of HIV-1 replication in neural cells and through indirect effects of HIV-1 infected macrophages on neural cells. Although they come from four different institutions, the Project and Core Leaders in this Program have a history of increasingly intense collaborations with each other that made this comprehensive Program possible. The major goals of the individual Projects are as follows: Project 1. To determine the molecular interactions engendering efficient HIV-1 replication in neural cells and their dysfunction. Project 2. To determine the molecular mechanisms through which HIV-1 infected macrophages and their products induce glial cell synthesis of neuronotoxins. Project 3. To employ (cultured neural cells) and explant model of fetal brain and to investigate the impact of HIV-1 replication, its cellular origin, and its tropism on neuropathogenesis. Project 4. To localize HIV-1 infection, its gene expression, and cellular gene modulation by in situ hybridization/PCR in brain sections from children who died of AIDS. Core 9001. To determine env, nef, vif sequences unique to brain tissue and construct chimeric viruses carrying them. Together these studies will use the detailed molecular mechanisms revealed in culture systems directly to probe analogous interactions in developing tissue and ex vivo to determine the basis for HIV-1 associated encephalopathy and its control.